ABSTRACT APOE4 is the greatest genetic risk for sporadic Alzheimer disease (AD), increasing risk up to 12-fold compared to APOE3. Further, APOE4 carriers often respond differently, sometimes negatively, in clinical trials. Thus, a major challenge facing modern science is developing therapeutic strategies for APOE4 carriers, and AD in general. The focus of this proposal is to target mechanistic processes that are AD-centric and further exacerbated by APOE4. Neurovascular (NV) dysfunction, including at the blood-brain barrier (BBB), is emerging as a critical component of AD progression. Although APOE modulates AD risk through multifactorial mechanisms, a role for APOE in NV dysfunction is increasingly evident. Indeed, our preliminary data in novel EFAD transgenic mice (express human APOE and 5xFamilial Alzheimer's disease (FAD) mutations) demonstrates that APOE4 and FAD induce cognitive dysfunction and NV leakiness in female mice by 8 months of age, significant as APOE4-induced AD risk is greater in females. Thus, our overarching hypothesis is that: APOE4 imparts a detrimental NV phenotype which can be overcome using targeted therapeutics. Accumulating evidence supports that repurposing antihypertensive therapeutics, particularly angiotensin receptor blockers (ARBs), is a promising treatment for AD through modulating the NV. In prospective studies ARBs are associated with a lower incidence and progression of AD, and ARBs have improved AD-like pathology in a limited number of AD-relevant models. However, clinically relevant questions for ARBs should be addressed in preclinical studies before repurposing for AD. One major issue is that no studies have tested ARBs in AD models that express human APOE. A second issue centers on whether beneficial effects of ARBs are: 1) systemic blood pressure-dependent, 2) systemic blood pressure-independent by acting directly on brain endothelial cells (BECs) at the BBB, 3) mediated via targets in the CNS, or combinational. Given that ARBs may exert functional effects on angiotensin receptors outside of vascular targets and blood pressure, specifically within the brain, it is important to consider brain penetration in preclinical studies. Indeed, although ARBs are considered poorly brain penetrant there is evidence of brain activity and therapeutically active brain bioavailability. In general, addressing the frequently overlooked issue of brain bioavailability and effects on efficacy is critical, highlighted by the recent failure of tarenflurbil and semagacestat in AD clinical trials, which show zero brain penetration. Proceeding to clinical trials without this information, particularly for drug repurposing, can result in failure and effectively end interest in a promising target. We hypothesize that repurposing or redesigning ARBs is an attractive therapy for AD, and may be particularly efficacious for APOE4 carriers. In Aim 1, the oral pharmacokinetics of ARBs will be measured assessed in wild type mice and in E4FAD mice at efficacious doses. In Aim 2, the efficacy and pharmacodynamics activity of ARBs will be assessed using treatment and prevention paradigms in EFAD mice.